1. Field of the Invention
The present invention relates to a method for treating catabolic, gut-associated pathological processes including intestinal mucosal and pancreatic atrophy and other disorders associated with enhanced gut permeability, impairment of host defenses, and compromised immune function. The invention further relates to a method for promoting recovery in subjects undergoing bone marrow transplantation.
2. Description of the Background Art
Catabolic processes (dysfunctions) are those physiological conditions in which the degradation of an anatomical structure occurs. Such conditions typically affect not only skeletal muscle, but also the lining of the gut. Catabolic activity resulting in tissue damage frequently follows surgery, sepsis, burn injury, cancer chemotherapy, radiation therapy/injury, or glucocorticoid therapy, often in association with inadequate food intake. such injuries, diseases, and treatments also typically result in compromised immune function.
In patients undergoing bone marrow transplantation, for example, the radiation and/or chemotherapeutic regimens pre- and post-transplant, coupled with the frequent occurrence of graft-versus-host disease, produce both catabolic and serious nutritional consequences. Many factors contribute to a requirement for total parenteral nutrition (TPN) in these patients, including oral and esophageal mucositis, diarrhea, nausea, vomiting, xerostomia, and dysgeusia (Cunninhgam et al., Nurs. Clin. N. Amer., 18:585-596 (1983); Cheney et al., Cancer 59:1515-1519 (1987)). Although TPN is believed to be necessary and beneficial in bone marrow transplant patients, trials with i.v. infusion of specialized formulas high in branched-chain amino acids (BCAA) during the first month after transplantation did not improve nitrogen balance (Lenssen et al., J. Parent. Ent. Nutr. 11:112-118 (1987)).
A catabolic response, damage to the gastrointestinal tract and compromised immune function brought on by the various causes listed above can be a major cause of death and disability. These clinical states are frequently associated with abnormal metabolism of the non-essential amino acid, glutamine (GLN). GLN can be synthesized to some extent by most tissues. Unlike most amino acids, GLN has two amine moieties: an alpha-amino group and an amide group. The presence of the amide group enables GLN to remove ammonia from the peripheral tissues of the body and transport nitrogen to visceral organs. In addition, it is common for tissues that remove GLN from the circulation to utilize the carbon skeleton for energy.
Glutaminase and glutamine synthetase are the two principal enzymes involved in the regulation of GLN metabolism. Glutaminase catalyzes the hydrolysis of GLN to glutamate and ammonia, while glutamine synthetase catalyzes the synthesis of GLN from glutamate and ammonia. While most tissues have both of these enzymes, usually one is more active than the other, depending on the particular tissue.
GLN synthesis and exportation occurs primarily in skeletal muscle and the brain. In turn, GLN is consumed by such replicating cells as fibroblasts, hemopoietic cells, lymphocytes, intestinal epithelium, and tumor cells. Characteristically, these cells possess high levels of glutaminase activity and low levels of intracellular GLN. This fact may have clinical significance for patients having large wounds, inflammation associated with infection, or a gastrointestinal dysfunction which precludes normal enteral feeding since the desirable proliferation of the cell types in these conditions may depend on the availability of sufficient levels of GLN.
In the gastrointestinal tract, GLN is used as a respiratory fuel. The enteral administration of GLN results in increased uptake of luminal GLN by the gut mucosa accompanied by a simultaneous decrease in uptake of GLN from the circulation. Thus, the consumption of GLN by the gut is balanced between these two sources of GLN.
Most of the GLN taken up by the gastrointestinal tract occurs via the epithelial cells lining the villi of the small intestine. The GLN metabolism which occurs in the small intestine provides a major source of energy for the gut and produces precursors for hepatic ureagenesis and gluconeogenesis by processing nitrogen and carbon from other tissues.
Baskerville et al. (Brit. J. Exp. Pathol., 61:132 (1980)) lowered the concentration of plasma GLN to undetectable levels by infusing purified glutaminase into rhesus monkeys, marmosets, rabbits, and mice, resulting in vomiting, diarrhea, villus atrophy, mucosal ulcerations, and intestinal necrosis
Martin et al. (U.S. Pat. No. 2,283,817) disclose a composition containing GLN which is used as a detoxicant, rather than a dietary supplement. In the patent, GLN is combined synergistically with other amino acids to act directly on a toxin to inhibit any deleterious effect.
In Shive et al. (U.S. Pat. No. 2,868,693), GLN-containing compositions for the treatment of peptic ulcers are disclosed.
Further evidence of the potential protective effect of GLN was shown by Okabe et al., Digestive Disease, 20:66 (1975), who found that GLN could protect against aspirin-induced gastric ulcerations in humans. These effects were not observed when GLN was given by tube feedings into the intestine, thus preventing direct exposure of the gastric mucosa to GLN. This indicates that the GLN effects on gastric ulceration were local and not secondary to altered systemic nutrition. The non-essential amino acid GLN is not present in standard parenteral alimentation solutions yet is a preferred oxidative fuel for the small intestine (Windmeuller, H. G., Adv. Enzyml. 53:201-237 (1982)) and has trophic effects on the intestinal mucosa of intravenously (i.v.) fed rodents (Hwang, T. L. et al., Surgical Forum 37:56-58 (1986); O'Dwyer, S. T. et al., Clin. Res. 35:369A (1987)). This visceral GLN requirement may be even greater during critical illness, when GLN metabolism by the small intestine is known to be increased (Souba et al., Surgery, 94(2):342 (1983)). Although GLN is known to be rapidly consumed by the pancreas and appears to be concentrated in the exocrine part of the gland (Cassano, G. B. et al., J. Neurochemistry 12:851-855 (1965)), the effect of exogenously administered GLN on the exocrine pancreas of intact animals has not been reported.
At present, the nutritional requirements of patients who are unable to feed themselves adequately are met through the administration of enteral or parenteral diets. Enteral diets are usually administered using small-bore tubing which is placed through the nose into the gastric, or duodenal regions, or through surgical implantation as in, for example, gastrostomy, or jejunostomy. Those enteral formulas which are presently available can be divided into four basic categories: elemental, polymeric, modular, and altered amino acids. These formulae contain GLN. The levels of nutrients present in the enteral diets, however, are generally based upon the dietary requirements of a normal individual and not that of a patient suffering from a catabolic disease.
Elemental formulas require minimal digestive action and are composed primarily of small peptides and/or amino acids, glucose oligosaccharides, and vegetable oil or medium-chain triglycerides.
In polymeric formulas, complex nutrients such as, for example, soy protein, lactalbumin, or casein are utilized as a source of protein; maltodextrins or corn syrup solids as a source of carbohydrate; and vegetable oils or milk fat as a source of fat.
Modular diets can be produced by combining protein, carbohydrate, or fat with a monomeric or polymeric formula to meet special nutritional requirements.
Formulas which are composed of altered amino acid compositions are used primarily for patients with genetic errors of nitrogen metabolism or acquired disorders of nitrogen accumulation, the object often being to limit the intake by the patient of certain amino acids which may be detrimental.
Parenteral diets are usually administered intravenously (i.v.). These i.v. fluids are sterile solutions composed of simple chemicals such as, for example, sugars, amino acids, and electrolytes, which can be easily assimilated.
The term "total parenteral nutrition" (TPN) is used to describe formulas for use in patients who derive their entire dietary requirements i.v. Total parenteral nutrition formulas, unlike enteral formulas, do not normally contain GLN. The absence of GLN from parenteral formulas is due, in part, to concern with respect to its instability at room temperature, and the resulting generation of ammonia and pyroglutamic acid. There has also been concern about the generation of glutamic acid from GLN because of the potential toxicity of glutamic acid as a neurotransmitter. In fact, these concerns do not appear to be justified at the pH values of enteral and parenteral nutrition solutions.
TPN results in villus atrophy, a phenomenon which is generally reversible when oral feedings are resumed. Since TPN formulas lack GLN, the body's requirements for this amino acid must be met from synthetic pathways in body tissues.
In patients with critical illnesses, net protein catabolism is associated with markedly diminished muscle GLN pools and reduced plasma GLN (Askanazi et al., Ann. Surg. 192:78 (1980); Askanazi et al., Ann. Surg., 191:465 (1980)), and a presumed increase in intestinal GLN utilization (Souba et al., Arch. Surg., 120:66 (1985); Souba et al., Surgery, 94(2):342 (1983)). Glucocorticoids also are known to increase GLN consumption by the small intestine (Souba et al., Surgical Forum, 34:74 (1983)).
TPN is associated with reduced pancreatic weight and diminished pancreatic exocrine secretion in addition to gastrointestinal mucosal atrophy (Hughes, C. A. et al., Clin. Science 59:329-336 (1980); Johnson, L. R. et al., Gastroenterology 68:1177-1183 (1975); Johnson, L. R. et al., Am. J. Physiol. 233:E524-E529 (1977); Towne, J. B. et al., Am. J. Surg. 126: 714-716 (1973)). Animals given sufficient nutrients i.v. to sustain body growth, develop as much pancreatic atrophy as occurs during starvation (Johnson, L. R. et al., (1975), supra). The etiology of pancreatic atrophy is poorly understood and may be secondary to various factors that normally accompany oral nutrient intake including: (1) the absence of luminal substrates (Clark, R. M., Clin. Sci. 50:139 (1976)); (2) lack of dietary amines (Seidel, E. R. et al., Am. J. Physiol. 249:G434-438 (1985)); (3) absence of fermentable fiber (Jacobs, L. R. et al., Am. J. Physiol. 246:G378- G385 (1984)); (4) alterations in neurohumoral processes (Johnson, L. R., Physiology of the Gastrointestinal Tract, 2d Ed., pp. 301-319, Raven Press, NY (1987)) or (5) changes in pancreaticobiliary secretions (Fine, H. et al., Am. J. Physiol. 245:G358-G363 (1983)). Additionally or alternatively, pancreatic atrophy may be influenced by the absence of specific nutrients in currently available parenteral alimentation solutions (Wilmore, W. W. et al., Surgery 104(5):917-923 (1988)).
Bone marrow transplantation is increasingly utilized in the treatment of hematologic malignancies (Thomas et al., Indications for bone marrow transplantation. Annu Rev Med 35:1-9 (1984)). Individuals undergoing bone marrow transplantation consistently lose body protein due to the catabolic effects of chemotherapy, total body irradiation and graft-versus-host disease, while gastrointestinal toxicity often limits consumption and absorption of enteral nutrients (Schmidt et al. Exp Hematol 8:506-11 (1980); Szeluga et al. JPEN J Parenter Enteral Nutr 9:139-43 (1985); Cheney et al. Cancer 59:1515-9 (1987); Weisdorf et al., J Pediatr Gastroenterol Nutr 3:95-100 (1984); and McDonald et al. Gastroenterology 90:460-84 (1986)). Infectious complications also remain a major cause of morbidity in marrow transplant patients (Meyers J. D., In: Mandell G. L., Douglas R. G., Bennett J. E. (ed): Principles and Practice of Infectious Diseases, 3rd edition. New York: Churchill Livingstone; pp. 2291-4. (1991)). Infection accelerates protein loss (Wilmore D. W., The Metabolic Management of the Critically Ill, 2 nd edition. New York: Plenum Medical Book Company, 1980.) and protein-calorie malnutrition may decrease host resistance to microbial invasion (Scrimshaw et al., Am J Med Sci. 237:367-403 (1973)).
Modification of amino acid formulations may improve clinical and metabolic efficacy of parenteral nutrition. In this study, we evaluate the effect of intravenous nutrition supplemented with glutamine. Glutamine is absent in all commercially available parenteral nutrient solutions, as it has a shorter shelf life than other amino acids commonly utilized and has been considered a nonessential amino acid. However, during catabolic states, glutamine concentrations in intracellular pools (primarily skeletal muscle) fall rapidly as glutamine is utilized for renal ammoniagenesis and serves as an oxidizable fuel for stimulated lymphocytes and macrophages and intestinal mucosal cells (Wilmore et al. Injured man: Trauma and sepsis. In: Winters R. W., ed. Nutritional Support of the Seriously Ill Patient. New York: Academic Press, pp. 33-52 (1983); Welbourne T. C., Am J Physiol 253:F1069-76 (1987); Windmueller H. G., Adv Enzymol 53:201-37 (1982); Newsholme et al. Nutrition 4:261-68 (1988)). Recent animal studies demonstrate that glutamine-enriched parenteral or enteral nutrition enhances nitrogen balance, attenuates intestinal mucosal damage, decreases bacteremia and improves survival following irradiation or chemotherapy when compared to glutamine-free nutrition (O'Dwyer et al. Clin Res 35:369A (1987); Klimberg et al. Cancer 66:62-8 (1990); Fox et al. JPEN J Parenter Enteral Nutr. 12:325-31 (1988); Fox et al. JPEN J Parenter Enteral Nutr. 12(suppl):8S (1987)). Limited clinical studies in postoperative patients have shown improved nitrogen retention with glutamine-enriched parenteral feeding (Stehle et al. Lancet i:231-23 (1989); Hammarqvist et al. Ann Surg 209:455-61 (1989)). The clinical safety of L-glutamine added as a component of balanced parenteral nutrient solutions has recently been documented (Ziegler et al. JPEN J Parenter Enteral Nutr. 14(suppl):137S-46S (1990)).
None of the prior art studies have shown that breakdown of skeletal muscle, atrophy of intestinal villi and of the pancreas, breakdown of the gut wall leading to enhanced permeability, compromised immune function, or other catabolic dysfunctions which occur during TPN can be prevented through the administration of high levels of GLN.